c h a p t e r

46
Hyperglycemic Crises:
Diabetic Ketoacidosis
and Hyperglycemic
Hyperosmolar State
Francisco J. Pasquel and Guillermo E. Umpierrez

CHAPTER OUTLINE
DIABETIC KETOACIDOSIS,  806 HYPERGLYCEMIC HYPEROSMOLAR STATE,  813
Epidemiology, 806 Epidemiology, 813
Pathophysiology, 806 Pathophysiology, 813
Precipitating Events,  808 Precipitating Events,  813
Diagnosis, 808 Diagnosis, 813
Treatment, 810 Treatment, 814
Complications, 812 Complications, 815
Prevention, 812 Prevention, 815

KEY POINTS
• D  KA is the most common and serious acute complications of diabetes, occurring in
patients with both type 1 and type 2 diabetes.
• DKA results from a combination of absolute or relative insulin secretion and increased
concentration of counterregulatory hormones
• Poor compliance with insulin therapy is the primary precipitating cause of DKA in
young adults. Other common precipitating causes are infections, cardiovascular events,
pancreatitis, surgery, and trauma.
• DKA is characterized by hyperglycemia (glucose >250 mg/dl), metabolic acidosis (pH
<7.30, bicarbonate <18 mEq/L), high anion gap (>14 mEq/L) and increased ketones
(beta-hydroxybutyrate >3mosm/L or positive acetoacetate)
• Management goals for DKA include correction of fluid deficit and electrolyte
imbalance; administration of intravenous insulin until resolution of hyperglycemia and
acid-based disorder; and search and treatment of the precipitating cause.
• HHS is the most common acute hyperglycemic emergency in elderly patients.
• HHS results from a combination of relative insulin secretion, impaired insulin action
due to increased concentration of counterregulatory hormones, and dehydration.
• Precipitating factors for HHS are similar to those for DKA.
• Diagnostic criteria for HHS are a plasma glucose concentration >600 mg/dL, a serum
osmolality >320 mOsm/kg, and the absence of ketoacidosis.
• Management goals for HHS include aggressive fluid replacement, intravenous insulin
administration until resolution of hyperglycemia, and search and treatment of the
precipitating cause.
  

805

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806 PART 5  DIABETES MELLITUS
Diabetic ketoacidosis (DKA) and hyperglycemic hyper-
osmolar state (HHS) are the most serious hyperglycemic
emergencies in patients with type 1 and type 2 diabetes.
Although DKA and HHS are discussed as separate enti-
ties, they represent points along a spectrum of hyper-
glycemic emergencies due to poorly controlled diabetes.
Both are characterized by insulinopenia and severe hyper-
glycemia, and they differ clinically only by the degree of
dehydration and the severity of metabolic acidosis.1-3 The
overall mortality in children and adult subjects with DKA
is less than 1%, but a mortality rate higher than 5% is
reported in older adults and in patients with concomi-
tant life-threatening illnesses.1 Mortality in patients with
HHS is higher than in those with DKA and is reported
in up to 20% in recent observational studies.4 Successful
treatment of both conditions requires frequent monitor-
ing, replacement of fluid and electrolyte deficits to restore
circulatory volume and tissue perfusion, correction of
hyperglycemia, and a careful search for the precipitating
cause. This chapter reviews recent advances in the patho-
physiology, epidemiology, diagnosis, clinical manifesta-
tions, management recommendations, and prevention of
DKA and HHS.
DIABETIC KETOACIDOSIS
Epidemiology
Diabetic ketoacidosis (DKA) is the most common and
serious acute complication of diabetes. DKA is respon-
sible for more than 140,000 hospital admissions per year
and 500,000 hospital days per year in the United States at
a substantial cost related to direct medical expenses and
indirect costs.1,5 Recent epidemiologic studies indicate
that hospitalizations for DKA are increasing, with most
cases occurring as recurrent cases in the same subjects.6-8
Treatment of DKA utilizes many resources, accounting
for an estimated annual total cost of $2.4 billion.1
Observational studies have reported that DKA
accounts for 4% to 9% of hospital discharges among
patients admitted with a primary diagnosis of diabetes.6,9
In a Danish study, the incidence was 8.5 per 100,000 total
population in the years 1975 to 1979.10 A higher figure
was reported by the EURODIAB study in which 8.6% of
3250 subjects with type 1 diabetes throughout Europe,
between 1989 and 1991, had an admission with DKA in
the previous 12 months.11 Worldwide incidence rates are
higher in populations with limited access to medical care
for social or economic reasons. In the United States, the
SEARCH for Diabetes in Youth Study found that 29.4%
of participants younger than 20 years of age with type 1
diabetes presented with DKA as compared to 9.7% of
youth with type 2 diabetes.12 Recent epidemiologic stud-
ies indicate that hospitalizations for DKA during the past
2 decades are increasing, with most cases occurring as
recurrent cases in the same subjects.6-8 In community-
based studies, more than 40% of adult patients with
DKA are older than 40 years of age and more than 20%
are older than 55 years of age.13 Patients with type 2 dia-
betes may develop DKA under stressful conditions such
as trauma, surgery, or infections13; however, an increas-
ing number of unprovoked ketoacidosis cases without
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precipitating cause have been reported in children and
adult subjects with type 2 diabetes.12 Unprovoked DKA
cases are more commonly reported in African Americans
and Hispanics,9,14-16 but have been reported in all eth-
nic groups.17-20 A helpful classification divides patients
with DKA into four categories, utilizing the presence or
absence of biomarkers of autoimmunity (A+ or –) and the
presence or absence of residual insulin secretory capacity
as evidenced by C-peptide release (β+ or –).21 Classic type
1 disease would be A+β–, whereas classic type 2 would
be A–β+.21,22
In children and adult subjects with DKA, the overall
mortality is less than 1%, but a mortality rate higher than
5% is reported in older adults and in patients with con-
comitant life-threatening illnesses.1 In adult patients with
diabetes, mortality increases substantially with aging,
with mortality rates for those between 65 and 75 years of
age reaching 10% to 20%.13 In the older age groups, the
major cause of death relates to the underlying medical ill-
ness (i.e., trauma, infection) that precipitated the ketoaci-
dosis, but in the younger patient, mortality is more likely
to be caused by metabolic disarray.
Pathophysiology
The mechanisms that trigger DKA are multifactorial and
include a combination of the reduced secretion and action
of insulin and the raised levels of counterregulatory hor-
mones (glucagon, catecholamines, cortisol, and growth
hormone).3,23 The insulin deficiency of DKA can be abso-
lute, as in type 1 diabetes or relative as in type 2 diabetes
in the presence of the increased release in counterregula-
tory hormones that causes a worsening of insulin resis-
tance and further impairment of insulin secretion.23,24
Ketogenesis and Ketoacidosis
The combination of insulin deficiency and glucagon
excess (elevated glucagon/insulin ratio) is critical for
the development of hyperglycemia and ketoacidosis.25
The increase in counterregulatory hormones leads
to the release of free fatty acids into the circulation
from adipose tissue (lipolysis) and to the unrestrained
hepatic fatty acid oxidation in the liver to ketone bodies
(Fig. 46-1).26,27 Insulin deficiency causes the activation of
hormone-sensitive lipase in adipose tissue. The increased
activity of tissue lipase causes the breakdown of triglyc-
eride into glycerol and free fatty acids. While glycerol
becomes an important substrate for gluconeogenesis in
the liver, the massive release of free fatty acids assumes
pathophysiologic predominance, as they are the hepatic
precursors of the ketoacids. In the liver, free fatty acids
are oxidized to ketone bodies, a process predominantly
stimulated by glucagon-induced generation of cAMP.
Increased concentration of glucagon lowers the hepatic
levels of malonyl coenzyme A (CoA) by blocking the con-
version of pyruvate to acetyl CoA through inhibition of
acetyl CoA carboxylase, the first rate-limiting enzyme in
the novo fatty acid synthesis. Malonyl CoA inhibits car-
nitine palmitoyl-transferase 1 (CPT 1), the rate-limiting
enzyme for transesterification of fatty acyl CoA to fatty
acyl carnitine,28 allowing the oxidation of fatty acids to
ketone bodies. CPT 1 is required for the movement of
 46  HYPERGLYCEMIC CRISES: DIABETIC KETOACIDOSIS AND HYPERGLYCEMIC HYPEROSMOLAR STATE 807

PATHOGENESIS OF DKA AND HHS

Absolute insulin Counterregulatory Relative insulin

deficiency hormones deficiency

↑ Hormone
sensitive
lipase ↑ Proteolysis
Absent or minimal
ketogenesis
↑ Gluconeogenic substrates
↑ Lipolysis ↑ Glycerol
(amino acids and lactate)

↑ FFA to liver ↓ Glucose utilization ↑ Gluconeogenesis ↑ Glycogenolysis

↑ Ketogenesis
(BOHB and AcAc) Hyperglycemia

Glycosuria (osmotic diuresis)

Ketoacidosis
Dehydration Hyperosmolarity

HHS

DKA

Figure 46-1  Pathogenesis of diabetic ketoacidosis (DKA). Hyperglycemia and ketogenesis result from a relative or absolute insulin deficiency com-
bined with excess levels of counterregulatory hormones including glucagon, cortisol, catecholamines, and growth hormone. Hyperglycemia develops
as a result of increased gluconeogenesis, generation of gluconeogenic precursors (alanine, amino acids, and glycerol), accelerated glycogenolysis,
and impaired glucose utilization by peripheral tissues. The accumulation of ketone bodies is caused by increased lipolysis and circulating free fatty
acids (FFAs). In the liver, FFAs are oxidized to ketone bodies, a process predominantly stimulated by glucagon. The two major ketone bodies are
β-hydroxybutyrate and acetoacetic acid. The accumulation of ketone bodies leads to a decrease in serum bicarbonate concentration and metabolic
acidosis. The ketosis and acidosis in DKA contribute to electrolyte disturbances, vomiting, and dehydration.

free fatty acid into the mitochondria, where fatty acid
oxidation takes place.28 The increased fatty acyl CoA
and CPT-1 activity in DKA lead to increased ketogenesis
in DKA. Increased production of ketone bodies (aceto-
acetate and β- hydroxybutyrate) leads to ketonemia and
metabolic acidosis.
Hyperglycemia
In normal subjects during the fasting state, plasma glu-
cose is maintained between 3.9 and 5.6 mmol/L (70 to
100 mg/dL) by a finely regulated balance between hepatic
glucose production and glucose utilization in peripheral
tissues (see Chapter 35). Insulin controls hepatic glucose
production by suppressing hepatic gluconeogenesis and
glycogenolysis. In insulin-sensitive tissues such as mus-
cle, insulin promotes protein anabolism, glucose uptake,
and glycogen synthesis, and it inhibits glycogenolysis
and protein breakdown. In addition, insulin is a power-
ful inhibitor of lipolysis, free fatty acid oxidation, and
ketogenesis. The counterregulatory hormones (glucagon,
catecholamines, cortisol, and growth hormone) promote
metabolic pathways opposite to those of insulin action,
both in the liver and in peripheral tissues.14
Hyperglycemia in patients with DKA develops as
a result of three processes: increased gluconeogenesis,
accelerated glycogenolysis, and impaired glucose uti-
lization by peripheral tissues (see Fig. 46-1).23 From
the quantitative standpoint, increased hepatic glucose
production represents the major pathogenic disturbance
in DKA.29 Increased hepatic glucose production results
from the high availability of gluconeogenic precursors,
such as amino acids (alanine and glutamine; as a result of
accelerated proteolysis and decreased protein synthesis),
lactate (as a result of increased muscle glycogenolysis),
and glycerol (as a result of increased lipolysis), and from
the increased activity of gluconeogenic enzymes (phos-
phoenol pyruvate carboxykinase [PEPCK], fructose-
1,6-bisphosphatase, and pyruvate carboxylase).30,31 The
activation of gluconeogenic enzymes appears to be pre-
dominantly stimulated by an increased synthesis of per-
oxisome proliferator-activated receptor-γ coactivator-1α
(PGC-1α) mediated by glucagon-induced production of
cAMP.32,33 Elevation of cAMP also causes a fall in fruc-
tose 2,6-bisphosphate (F-2,6-P2) leading to inhibition of
phosphofructokinase (PFK), a key regulatory enzyme in
the glycolytic pathway.34
In addition to insulin deficiency, an increase in coun-
terregulatory hormones plays an important role in glu-
cose overproduction in DKA. Elevated glucagon and
catecholamine levels lead to increased gluconeogenesis
and glycogenolysis.35-37 Epinephrine stimulates gluca-
gon secretion and inhibits insulin release by pancreatic
β-cell secretion.23,24 High cortisol levels stimulate protein
catabolism and increased circulating amino acid concen-
tration, providing precursors for gluconeogenesis.38,39
In addition, increased glucose levels cause osmotic

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808 PART 5  DIABETES MELLITUS

diuresis, which contributes to dehydration, hypovolemia, TABLE 46-1  Diagnostic Criteria for Diabetic
and decreased glomerular filtration rate, which further Ketoacidosis (DKA) and Hyperglycemic
increase the severity of the hyperglycemia. Hyperosmolar State (HHS)
The development of hyperglycemia and ketoacido-
sis results in an inflammatory state characterized by an DIAGNOSTIC CRITERIA AND CLASSIFICATION
elevation of proinflammatory cytokines and increased DKA
oxidative stress markers.40,41 Circulating levels of tumor Mild Moderate Severe HHS
necrosis factor-α; interleukin [IL]-6, IL1-β, and IL-8; and
C-reactive protein are significantly increased twofold to Plasma glucose >250 >250 >250 >600
(mg/dL)
fourfold on admission in patients with hyperglycemic cri- Arterial pH 7.25- 7.00- <7.00 >7.30
ses compared with control subjects, and levels returned to 7.30 <7.24
normal after insulin treatment and resolution of hypergly- Serum bi- 15-18 10-<15 <10 >15
cemic crises.40 TNF-α probably contributes to the insulin carbonate
resistance of DKA through the altered regulation of the (mEq/L)
Urine ketone Positive Positive Positive Small
insulin-signaling pathway and by interaction at the level Serum ketone Positive Positive Positive Small
of the insulin receptor itself.42-44 TNF-α causes a moder- Effective serum Variable Variable Variable >320
ate decrease in the insulin-stimulated autophosphoryla- osmolality mOsm/
tion of the insulin receptor and a significant reduction in kg
Anion gap >10 >12 >12 <12
tyrosine phosphorylation of insulin receptor substrate-1 Alteration in Alert Alert/ Stupor/ Stupor/
(IRS-1). Activation of c-Jun NH2-terminal kinase (JNK) sensorium Drowsy Coma Coma
by TNF-α mediates serine phosphorylation of IRS-1, pre- or mental ob-
venting insulin-mediated activation of phosphatidylinosi- tundation
tol 3-kinase (PI 3-kinase), a key regulator of tissue glucose
uptake. Similarly, elevated fatty acids during DKA could
stimulate phosphorylation of IRS-1 on its serine resi- decrease in bicarbonate, stress, and increased production
dues,45 leading to a worsening of insulin resistance. of human placental lactogen, prolactin, and cortisol.49,50
Increased oxidative stress and generation of reactive The importance of noncompliance and psychological
oxygen species (ROS) during acute illness can lead to cel- factors in the incidence of DKA has been particularly
lular damage of lipids, membranes, proteins, and DNA. apparent in younger patients. In adult patients with
Oxidative stress decreases the expression and activity of type 1 diabetes, poor adherence to the diabetes treat-
key transcription factors that regulate genes involved in ment program is also the major precipitating cause of
β-cell function.46 The increased inflammatory state in DKA.8,51 In a recent prospective study, discontinuation
DKA can lead to capillary perturbation through the acti- of insulin therapy accounted for more than two-thirds
vation of vasoactive peptides, like endothelin 1, vascular of DKA admissions. Several behavioral, socioeco-
endothelial growth factor (VEGF), and ICAM-1 expres- nomic, and psychosocial factors contributed to poor
sion influenced by ketones bodies.47,48 This may explain treatment adherence. Psychiatric disorders, such as
why hyperglycemia is associated with poor vascular out- depression, anxiety, and eating disorders are common
comes in hyperglycemic patients.41 among patients with type 1 diabetes; and the history of
a psychiatric disorder can double the risk for having a
Precipitating Events DKA episode.52 Studies have reported eating disorders
DKA is the initial manifestation of diabetes in 20% of in up to 20% of recurrent episodes of ketoacidosis in
adult patients and in 30% to 40% of children with type young women.
1 diabetes. In known diabetic patients, precipitating fac- Diagnosis
tors for DKA include infections, intercurrent illnesses,
psychological stress, and poor compliance with therapy. Symptoms and Signs
Infection is the most common precipitating factor for The clinical manifestations are polyuria, polydipsia, signs
DKA, occurring in 30% to 50% of cases (Table 46-1). of dehydration, and progressive deterioration of mental
Urinary tract infection and pneumonia account for most status leading to a coma. Abdominal pain, sometimes
infections. Other acute conditions that may precipitate mimicking an acute abdomen, is reported in 40% to
DKA include cerebrovascular accident, alcohol abuse, 75% of cases of DKA.53 Nausea, vomiting, and abdomi-
pancreatitis, pulmonary embolism, myocardial infarc- nal pain are commonly seen in DKA and are likely to be
tion, and trauma. Drugs that affect carbohydrate metabo- caused largely by the combined effects of dehydration,
lism such as corticosteroid, thiazides, sympathomimetic ketonemia, and delayed gastric emptying. The presence of
agents, and pentamidine may also precipitate the devel- abdominal pain is associated with more severe metabolic
opment of DKA, as well as the use of atypical antipsy- acidosis, but not with the severity of hyperglycemia.53
chotic agents.8 Pregnant women with diabetes are also Urine output occurs until extreme volume depletion leads
at higher risk compared to nonpregnant diabetic women. to a critical decrease in renal blood flow and glomerular
Risk factors that can predispose pregnant women include filtration.
accelerated starvation, dehydration, nausea or hypereme- Physical examination reveals signs of dehydration,
sis gravidarum, decreased buffering capacity as a result including loss of skin turgor, dry mucous membranes,
of increased pulmonary ventilation and compensatory tachycardia, and hypotension. Acetone on the breath and

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 46  HYPERGLYCEMIC CRISES: DIABETIC KETOACIDOSIS AND HYPERGLYCEMIC HYPEROSMOLAR STATE 809

PROTOCOL FOR MANAGEMENT OF ADULT PATIENTS WITH DIABETIC KETOACIDOSIS (DKA)

IV fluids Insulin Potassium

Administer 0.9% NaCl Regular, 0.1 U/kg as IV bolus If serum K+ is <3.3 mEq/L,
(500–1000 ml/hr) hold insulin and give 10–20
during the first 1–2 hrs mEq per hour of KCl until
serum K+ ≥ 3.3 mEq/L

Evaluate corrected serum Na+

0.1 U/kg/hour IV insulin infusion
If serum K+ > 5.0 mEq/L,
Na+ Na+ do not give K+ but check
Serum Serum Na+ Serum
high low serum K+ q 2 hr
normal Check serum glucose every 1–2 hours.
When serum glucose reaches 200 mg/dl

0.45% NaCl at 250–500 0.9% NaCl at 250–500 If serum K+ between 3.3

mL/hr depending on state mL/hr depending on state and 5.0 mEq/L, give 20–30
of hydration of hydration mEq of KCl in each liter of
IV fluid to keep serum K+ at
4–5 mEq/L

When serum glucose reaches 200 mg/dl

Change to 5% dextrose with 0.45% NaCl and

decrease insulin to 0.05–0.1 U/kg/hr to maintain
Check Chem 7 and venous pH every 2–4 hrs until resolution of DKA.
serum glucose between 150–200 mg/dl
Initiate SC insulin when the patient is alert and can eat. Identify and
until resolution of ketoacidosis*
treat precipitating cause.

*Resolution of ketoacidosis = blood glucose < 250 mg/dl, bicarbonate > 18 mEq/L, and pH > 7.30.
Figure 46-2  Protocol for management of patients with diabetic ketoacidosis (DKA).

labored Kussmaul respiration characterized by rapid, deep
respirations in response to metabolic acidosis is frequently
found in children and in adults with severe metabolic aci-
dosis. Mental status can vary from full alertness to pro-
found lethargy; however, fewer than 20% of patients are
hospitalized with loss of consciousness.7,23 Hypothermia,
potentially caused by a failure of heat production as a result
of impaired oxygen consumption, is not uncommon, and
can potentially aggravate ketoacidosis.54,55 Hypothermia
has been associated with a decrease in insulin secretion55a
and glucose utilization,55b and with an increase in counter-
regulatory hormones.55c,55d The presence of a fever is
highly suggestive of a concomitant infection.
Laboratory Findings
The syndrome of DKA consists of the triad of hypergly-
cemia, ketonemia, and metabolic acidosis.1 DKA can
be classified as mild, moderate, or severe, depending on
the extent of metabolic acidosis and the level of senso-
rium (see Table 46-1). The severity of metabolic acidosis
bears small relationship to the degree of hyperglycemia,
and cases of ketoacidosis with normal or only modestly
elevated glucose levels (<13.8 mmol/L, 250 mg/dL) have
been reported.56 This phenomenon has been reported
during pregnancy, in patients with prolonged starvation,
and in those who present after receiving insulin. Simi-
larly, relatively low glucose concentrations may occur in
the presence of impaired hepatic glucose output, such as
in patients with alcohol abuse or liver failure.57,58
The key diagnostic feature is the elevation of circulat-
ing total blood ketone concentration. Assessment of keto-
nemia is usually performed by the nitroprusside reaction,
which provides a semiquantitative estimation of acetoac-
etate and acetone levels. Although the nitroprusside test
(urine and serum) is highly sensitive, it can underestimate
the severity of ketoacidosis because this assay does not
recognize the presence of β-hydroxybutyrate, the main
metabolic product in ketoacidosis.31,59 If available, mea-
surement of serum beta-hydroxybutyrate may be useful
for diagnosis.60 Recently, it was reported that home capil-
lary blood β-hydroxybutyrate testing is more effective than
urine acetoacetate testing in reducing emergency visits,
hospitalization, and the time to recovery from DKA.61,62
The accumulation of ketoacids results in an increased
anion gap metabolic acidosis. The anion gap is calculated by
subtracting the sum of the chloride and bicarbonate concen-
tration from the sodium concentration [Na+ – (Cl− + HCO3−)]
(Fig. 46-2). A normal anion gap is between 7 and 9 mEq/L,
and an anion gap greater than 12 mEq/L indicates the pres-
ence of increased anion gap metabolic acidosis.23 Although
most subjects with DKA present with a high anion gap aci-
dosis, it is important to keep in mind that patients may pres-
ent with mixed acid-base disorders. It has been reported that
11% of patients admitted with DKA had hyperchloremic

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810 PART 5  DIABETES MELLITUS
TABLE 46-2  Useful Formulas for the Evaluation
of Diabetic Ketoacidosis and Hyperglycemic
Hyperosmolar State
1. Calculation of anion gap (AG):
[ ]
AG = Na + − [Cl − + HCO3 − ]
2. Total and effective serum osmolality:
[ ]
2 Na + + glucose (mg/dL) BUN (mg/dL)
Total = +
18 2.8
[ ] glucose (mg/dL)
Effective = 2 Na + +
18
3. Corrected serum sodium:
[
Corrected Na + =
] 1.6 × glucose (mg/dL) − 100
[ 100]
+ measured Na +
4. Total Body Water (TBW) deficit:
[ ]
corrected Na + − 1
TBW deficit = [weight (kg) × 0.6] −
140
metabolic acidosis (normal anion gap along with decreased
bicarbonate and elevated chloride levels), 43% had mixed
anion gap acidosis and hyperchloremic metabolic acidosis,
and 46% had predominant anion gap acidosis.63 More
important, during the treatment and resolution of DKA,
most patients develop a transient hyperchloremic non–
anion gap metabolic acidosis.58,64
Patients with DKA have an extracellular fluid vol-
ume deficit usually in the range 4% to 10%.65-68 Clinical
estimates of the volume deficit are subjective and inac-
curate,67,69,70 and the magnitude of dehydration cannot
be assessed accurately by either clinical or biochemical
parameters. Calculation of effective osmolality [sodium
ion (mEq/L) × 2 + glucose (mg/dL)/18] is the best marker
of volume depletion, and levels greater than 320 mmol/L
are frequently associated with impaired mental status
(Table 46-2).
The admission serum sodium is usually low because
of the osmotic flux of water from the intracellular to
the extracellular space in the presence of hyperglyce-
mia. To assess the severity of sodium and water deficit,
serum sodium may be corrected by adding 1.6 mg/dL to
the measured serum sodium for each 100 mg/dL of glu-
cose above 100 mg/dL (see Table 46-2).23 An increase in
serum sodium concentration in the presence of hypergly-
cemia indicates a profound degree of water loss.
The admission serum potassium concentration is usu-
ally elevated in patients with DKA.23 These high levels
occur because of a shift of potassium from the intracel-
lular to the extracellular space caused by acidemia, insu-
lin deficiency, and hypertonicity. Similarly, the admission
serum phosphate level may be normal or elevated because
of metabolic acidosis.
Patients with DKA frequently present with leukocy-
tosis in the absence an infection. However, a leukocyte
count greater than 25,000 mm3 or the presence of greater
than 10% neutrophil bands is seldom seen in the absence
of a bacterial infection.1,23 Because most patients with
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DKA present with abdominal pain, nausea, or vomiting,
the differential diagnosis of acute pancreatitis should be
considered. Increased amylase levels are reported in 21%
to 79% of patients with DKA. There is little correlation
between the presence, degree, or isoenzyme type of hyper-
amylasemia and the presence of symptoms or pancreatic
imaging studies; therefore, an increased serum amylase is
not definitive for the diagnosis of pancreatitis in DKA.53
Nonspecific serum lipase elevation has also been reported
in one-third of patients with DKA in the absence of clini-
cal and radiologic evidence of acute pancreatitis.53
Not all patients who present with anion gap acidosis
or ketoacidosis have DKA.2 Patients with chronic ethanol
abuse with a recent binge culminating in nausea, vom-
iting, and acute starvation may present with alcoholic
ketoacidosis. The key diagnostic feature that differen-
tiates diabetic and alcohol-induced ketoacidosis is the
concentration of blood glucose.58 Whereas DKA is char-
acterized by severe hyperglycemia, the presence of keto-
acidosis without hyperglycemia in an alcoholic patient is
virtually diagnostic of alcoholic ketoacidosis. In addition,
some patients with decreased food intake (lower than 500
calories/day) for several days may present with starva-
tion ketosis. However, a healthy subject is able to adapt
to prolonged fasting by increasing ketone clearance by
peripheral tissue (brain and muscle) and by enhancing the
kidney’s ability to excrete ammonia to compensate for
the increased acid production. Therefore, a patient with
starvation ketosis rarely presents with a serum bicarbon-
ate concentration less than 18 mEq/L.
Treatment
Figure 46-2 shows the American Diabetes Association
algorithm for the treatment of DKA.1 The goals of DKA
therapy are as follows: 1) to improve circulatory volume
and ultimately tissue perfusion, 2) to correct hyperglyce-
mia by gradually decreasing serum glucose and plasma
osmolarity, 3) to correct electrolyte imbalance and
increased serum ketone bodies, and 4) to identify and
treat precipitating events. Frequent monitoring of vital
signs, volume, and rate of fluid administration, insulin
dosage, urine output, and assessing the response to medi-
cal treatment are essential for the successful management
of DKA. Serial laboratory measurements include glucose,
electrolytes, venous pH, bicarbonate, and anion gap val-
ues until the resolution of ketoacidosis.
There are no guidelines for determining the safety
and cost-effectiveness of treating adult patients with
DKA in ICU or non-ICU settings. Several observational
and prospective studies have indicated no clear benefits
in treating DKA patients in the ICU compared to step-
down units or general medicine wards.71-73 The mor-
tality rate, length of hospital stay, or time to resolve
ketoacidosis is similar in patients treated in ICU and
non-ICU settings. In addition, ICU admission has been
shown to be associated with more testing and a sig-
nificantly higher hospitalization cost in patients with
DKA.71,74 Thus, patients with mild to moderate DKA
can be safely managed in emergency departments or
step-down units, and only patients with severe DKA
or those with a critical illness as a precipitating cause
 46  HYPERGLYCEMIC CRISES: DIABETIC KETOACIDOSIS AND HYPERGLYCEMIC HYPEROSMOLAR STATE
(i.e., myocardial infarction, gastrointestinal bleeding,
sepsis)1,75 can be treated in the ICU.
Fluid Therapy
Patients with DKA are volume depleted with an estimated
water deficit of ∼100 mL/kg of body weight.23 Aggressive
fluid therapy expands intravascular volume, restores renal
perfusion, and improves insulin sensitivity by reducing
circulating counterregulatory hormones. Isotonic saline
(0.9% NaCl) at a rate of 500 to 1000 mL/hour during
the first 1 to 2 hours is usually sufficient to restore blood
pressure and renal perfusion. The subsequent choice and
rate of fluid replacement depends on hemodynamics, the
state of hydration, serum electrolyte levels, and urinary
output. In general, 0.45% NaCl infused at 250 to 500
mL/hour is appropriate if the corrected serum sodium is
normal or elevated; 0.9% NaCl at a similar rate is appro-
priate if the corrected serum sodium is low.23 (see Fig.
46-2). Once the plasma glucose is ∼250 mg/dL, 5% to
10% dextrose should be added to replacement fluids to
allow continued insulin administration until ketonemia
is controlled, while at the same time avoiding hypogly-
cemia.1 The water deficit can be estimated, based on cor-
rected serum sodium concentration, using the following
equation:
water deficit = (0.6) (body weight in kilograms)
× (1 − [corrected sodium/140]). 23
The goal is to replace half the estimated water def-
icit over a period of 24 hours. The administration of
large amounts of isotonic saline, which contains a high
content of chloride, can lead to hyperchloremic meta-
bolic acidosis caused by the acidifying effect of saline by
the excessive administration of Cl− ions.76 Preliminary
studies with the use of lactated Ringer’s solution have
reported a reduction of hyperchloremic acidosis,76,77 but
such a reduction has not been shown to improve out-
come or to reduce hospital length of stay compared to
saline administration.
Insulin Therapy
Insulin administration is the cornerstone of DKA ther-
apy. Insulin increases peripheral glucose utilization and
decreases hepatic glucose production, as well as inhibits
the release of FFA from adipose tissue and decreases keto-
genesis. Randomized controlled studies in patients with
DKA have shown that lower doses of insulin therapy,
compared to very high doses used decades ago, are effec-
tive regardless of the route of administration.78,79 A com-
mon and effective practice includes an initial IV bolus of
regular insulin of 0.1 unit/kg of body weight, followed
by a continuous infusion of regular insulin at a dose of
0.1 unit/kg/hour.1 A recent study reported that the initial
bolus is not necessary if the hourly insulin infusion rate is
started at 0.14 units/kg body weight.80 When the serum
glucose has declined to about 250 mg/dL, the insulin infu-
sion rate should be reduced to 0.05 units/kg/hour. There-
after, the rate of insulin administration may need to be
adjusted to maintain glucose levels at approximately 200
mg/dL and continued until ketoacidosis is resolved.
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811
A patient with uncomplicated DKA can be treated with
subcutaneous (SC) rapid-acting insulin lispro or insulin
aspart.73 These studies indicate that after an initial SC dose
of 0.2 to 0.3 units/kg, the administration of 0.1 or 0.2 units/
kg every 1 or 2 hours, respectively, is as effective as the
continuous infusion of regular insulin. This is done in the
emergency department or in non-ICU wards if adequate per-
sonnel are available for frequent glucose monitoring.
Potassium
Patients with DKA have an estimated total potassium def-
icit of ∼3 to 5 mEq/kg of body weight. Despite this deficit,
most patients with DKA have a serum potassium level at
or above the upper limits of normal.1 These high levels
occur because of a shift of potassium from the intracellu-
lar to the extracellular space caused by acidemia, insulin
deficiency, and hypertonicity. Both insulin therapy and
the correction of acidosis decrease potassium levels by
stimulating cellular potassium uptake in peripheral tis-
sues and by increasing urinary excretion.81 Intravenous
potassium should be initiated when serum concentration
is below 5.0 mEq/L. The treatment goal is to maintain
serum potassium levels within the normal range of 4 to
5 mEq/L.1 Generally, 20 to 30 mEq of potassium chlo-
ride in each liter of infusion fluid is sufficient to main-
tain a potassium concentration within the normal range.
To prevent severe hypokalemia and the risk for cardiac
arrhythmias, patients with a serum potassium lower than
3.3 mEq/L should receive potassium replacement at a
rate of 10 to 20 mEq/hour, and insulin infusion should be
delayed until potassium is >3 mEq/L.
Bicarbonate
Several studies have evaluated the effect of alkalinization
in patients with DKA and have reported no advantage of
bicarbonate therapy in improving cardiac and neurologic
functions or improving the rate of recovery of hyperglyce-
mia and ketoacidosis.82-90 Moreover, bicarbonate therapy
can lead to higher a risk for hypokalemia, decreased tissue
oxygen uptake, and cerebral edema.1 However, because
severe acidosis may result in impaired myocardial con-
tractility, cerebral vasodilatation, and coma, recent treat-
ment guidelines recommend that in patients with severe
metabolic acidosis (pH <6.9), 50 to 100 mmol of sodium
bicarbonate should be given as an isotonic solution (in
200 mL of water) every 2 hours until the pH rises to ∼6.9
to 7.0. In patients with arterial pH >7.0, no bicarbonate
therapy is necessary.
Phosphate and Magnesium
Severe hypophosphatemia may lead to rhabdomyolysis,
hemolytic uremia, and muscle weakness; however, sev-
eral studies have failed to show any beneficial effect of
phosphate replacement on clinical outcome. Furthermore,
aggressive phosphate therapy is potentially hazardous, as
indicated in case reports of children with DKA who devel-
oped hypocalcemia and seizures secondary to intravenous
phosphate administration. Phosphate replacement should
be reserved for patients with cardiac dysfunction, anemia,
respiratory depression, and a serum concentration lower
than 1.0 to 1.5 mg/dL.1
812 PART 5  DIABETES MELLITUS
Patients with DKA frequently have large magnesium
deficits, but there are no data to determine whether
replacement of magnesium is beneficial in improving
clinical outcome. Replacement of magnesium should be
considered in the occasional patient with severe hypo-
magnesemia and hypocalcemia. The recommended dose
is 25 to 50 mg/kg for 2 to 4 doses given every 4 to 6 hours
with a maximum infusion rate of 2 g/hour.
Transition to Subcutaneous Insulin
Intravenous insulin therapy should continue until the
hyperglycemic crisis has resolved. Criteria for the reso-
lution of DKA include a blood glucose lower than 200
mg/dL, a serum bicarbonate equal to or greater than 18
mEq/L, and a venous pH greater than 7.3. When this
occurs, SC insulin therapy can be started.
It is important to recognize that the half-life of intrave-
nous insulin is ∼5 to 7 minutes; therefore, if insulin infu-
sion is interrupted suddenly, the insulin concentration in
blood could reach undetectable levels, with relapse of the
hyperglycemia and ketoacidosis. Therefore, insulin infu-
sion should be continued for 2 to 4 hours after SC insulin
is started. A recent study reported that basal insulin given
a few hours after starting insulin infusion facilitates treat-
ment and prevents the rebound of hyperglycemia after
discontinuation of IV insulin therapy.91
The best time to transition to SC insulin is when the
patient is alert and able to take food by mouth. Patients
previously treated with insulin can resume their previous
regimen. Insulin-naïve adult patients can be started on
0.5 to 0.7 units/kg/day, in divided doses, to achieve ade-
quate glucose control.1 The basal prandial approach with
insulin basal (lantus or detemir) and rapid-insulin (lispro,
aspart, glulisine) analogues is the preferred treatment regi-
men after the resolution of DKA. An alternative is the use
of a split-mixed insulin regimen with neutral protamine
Hagedorn (NPH) and regular insulin twice daily or of a
multi-dose regimen of short- or rapid-acting and interme-
diate- or long-acting insulins.1 A recent randomized study
compared the safety and efficacy of insulin analogues and
human insulin during the transition from intravenous to SC
insulin in patients with DKA. There were no differences in
mean daily glucose levels, but 41% of patients treated with
NPH and regular insulin experienced one or more hypo-
glycemic events compared to 15% of patients treated with
insulin analogues. Thus, a basal bolus regimen with insulin
analogues is safer and should be preferred over NPH and
regular insulin following the resolution of DKA.92
Complications
The two most common complications associated with
the treatment of DKA in adult subjects are hypoglycemia
and hypokalemia. Hypoglycemia is reported in 10% to
25% of patients during insulin therapy. Hypoglycemia
is reported in 10% to 30% of patients with DKA, with
the majority of hypoglycemic events occurring after sev-
eral hours of insulin infusion (between 8 and 16 hours)
or during the transition phase. The failure to reduce the
insulin infusion rate and the failure to use dextrose-con-
taining solutions when glucose levels reach 250 mg/dL
are the two most common causes of hypoglycemia during
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insulin therapy. Frequent blood glucose monitoring dur-
ing insulin infusion (every 1 to 2 hours) is mandatory
to recognize hypoglycemia because many patients with
DKA do not experience the adrenergic manifestations of
sweating, nervousness, hunger, or tachycardia.
The relapse of DKA may occur after the sudden inter-
ruption of IV insulin therapy or in patients without con-
comitant use of SC insulin administration or the lack
of frequent monitoring. To prevent recurrence of keto-
acidosis during the transition period to SC insulin, it is
important to allow an overlap of 2 to 4 hours between
discontinuation of IV insulin and the administration
of SC regular insulin. Other complications of diabetes
include hyperchloremic acidosis with an excessive use of
NaCl or KCl, resulting in a non–anion gap metabolic aci-
dosis. This acidosis has no adverse clinical effects and is
gradually corrected over the subsequent 24 to 48 hours
by enhanced renal acid excretion. The development of
hyperchloremia can be prevented with the reduction of the
chloride load by judicious use of hydration solutions.23
Cerebral injury is the most serious complication in chil-
dren and occurs in approximately 1% of children with
DKA93,94 (see Chapter 49); however, this is seldom reported
in adult patients with DKA.95 Symptoms and signs of cere-
bral edema are variable and include the onset of headache,
gradual deterioration in level of consciousness, seizures,
sphincter incontinence, pupillary changes, papilledema,
bradycardia, elevation in blood pressure, and respiratory
arrest. Cerebral edema typically occurs 4 to 12 hours after
treatment is activated, but it can be present before treat-
ment has begun or may develop any time during treatment
for DKA.94 Although no single factor has been identified
that can be used to predict the development of cerebral
edema, mechanisms have been proposed, including the role
of cerebral ischemia and hypoxia, the generation of vari-
ous inflammatory mediators, an increased cerebral blood
flow, the disruption of cell membrane ion transport, and
a rapid shift in extracellular and intracellular fluids that
results in changes in osmolality.
Rhabdomyolysis may occur in patients with DKA
and more commonly with HHS resulting in acute kidney
failure, severe hyperkalemia, hypocalcemia, and muscle
swelling causing compartment syndrome. The classic
symptom triad of rhabdomyolysis includes myalgia,
weakness, and dark urine. Monitoring creatine kinase
concentrations every 2 to 3 hours is recommended for
early detection. In pediatric patients, rhabdomyolysis has
been associated with a not well-understood malignant
hyperthermia–like syndrome.96
Prevention
The most common precipitating causes of DKA include
infection, intercurrent illness, psychological stress, and
noncompliance with therapy. With improved outpatient
treatment programs and better adherence to self-care,
∼50% to 75% of DKA admissions may be preventable.
Outpatient management is more cost-effective and can
minimize missed days of school and work for patients
with diabetes and their family members. The frequency of
hospitalizations for DKA has been reduced following dia-
betes education programs, improved follow-up care, and
 46  HYPERGLYCEMIC CRISES: DIABETIC KETOACIDOSIS AND HYPERGLYCEMIC HYPEROSMOLAR STATE
access to medical advice. Many patients with recurrent
DKA are unaware of sick-day management or the conse-
quences of skipping or discontinuing insulin therapy.97 It
has been shown that quarterly visits to the endocrine clinic
will reduce the number of emergency department admis-
sions for DKA. An important feature of patient education
is how to deal with illness. This includes 1) communicat-
ing the importance of insulin therapy during illness and
emphasizing that insulin should never be discontinued,
2) initiating early contact with health care providers, 3)
initiating early management of fevers and infections, and
4) ensuring adequate fluid intake.23 Diabetes education
and sick-day management should be reviewed periodi-
cally in patients with type 1 diabetes and should include
specific information on when to contact the health care
provider, the use of supplemental short- or rapid-acting
insulin during illness, and, most imperative, the impor-
tance of never discontinuing insulin. Patients with type 1
diabetes should be instructed on the use of home blood
ketone monitoring (if available) during illness and per-
sistent hyperglycemia, which may allow for early recog-
nition of impending ketoacidosis. Beta-hydroxybutyrate
testing (capillary blood test) seems to be more effective
than urine acetoacetate testing in reducing emergency
department visits and hospitalizations.61
HYPERGLYCEMIC HYPEROSMOLAR STATE
Epidemiology
The hyperglycemic hyperosmolar state (HHS) or hyper-
glycemic hyperosmolar nonketotic coma (HHNK) is a
serious and potentially lethal acute complication of dia-
betes.98 Cases of diabetic coma without the clinical fea-
tures of ketoacidosis were initially described in the late
1800s; however, the importance of hyperosmolality as an
essential component of the syndrome was not recognized
until the late 1950s.99,100 Mortality in patients with HHS
has decreased in recent decades, but remains higher than
in patients with DKA.4,7,101-110 A recent observational
study reported a weighted average mortality of 17.4% in
1284 adult cases of HHS.4 More pediatric cases are being
diagnosed, with a mortality as high as 37%.111,112
Pathophysiology
The pathophysiology of HHS is similar to that reported
in DKA. Insulin deficiency and increased counterregu-
latory hormones lead to increase gluconeogenesis and
decreased glucose uptake in peripheral tissues. The long
duration and severity of hyperglycemia in HHS results in
severe dehydration, hyperosmolality and impaired renal
function, which lead to decreased excretion of glucose. It
is speculated that higher levels of circulating insulin and
lower levels of counterregulatory hormones in patients
with HHS can explain the absent or minimal ketosis,
which is the key difference from DKA. In general, three
major mechanisms have been proposed for the lack of
ketoacidosis in HHS3,23,81,103,113-115 and include: 1) higher
levels of endogenous insulin in HHS (i.e., adequate insu-
lin concentration to prevent lipolysis but inadequate to
inhibit hepatic glucose production and/or stimulate glu-
cose use); 2) lower levels of counterregulatory hormones
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813
and free fatty acids; and 3) inhibition of lipolysis by the
hyperosmolar state, thereby decreasing ketogenesis.
Precipitating Events
HHS occurs most commonly in older subjects with type 2
diabetes, but may be seen in younger and in type 1 patients
as well. Up to 20% of patients admitted with HHS do not
have a previous diagnosis of diabetes.7 The most com-
mon precipitating causes are pneumonia and urinary
tract infection, accounting for 30% to 50% of cases.116-
118 Other acute medical illnesses as precipitating causes
include acute coronary syndromes, trauma, surgery, and
cerebrovascular accident, which provoke the release of
counterregulatory hormones and/or compromise access
to water. Certain medications that cause DKA may also
precipitate the development of HHS, including glucocor-
ticoids, thiazide diuretics, Dilantin, and β-blockers.119,120
During the last few years, several case reports and retro-
spective studies suggest an increased risk for developing
diabetes mellitus in patients treated with atypical anti-
psychotics compared to schizophrenic patients treated
with conventional antipsychotics or those without treat-
ment.121-123 Most cases of hyperglycemic crises associated
with the use of antipsychotics have been reported during
treatment with clozapine and olanzapine.124-126
Diagnosis
Symptoms and Signs
The typical patient with HHS has undiagnosed diabetes,
is between 55 and 70 years of age, and frequently is a
nursing home resident. Most patients who develop HHS
do so over days to weeks during which they experience
polyuria, dehydration, and a progressive decline in level
of consciousness. Physical examination reveals signs of
volume depletion. Fever caused by underlying infection
is common, and signs of acidosis (Kussmaul respirations,
acetone breath) are usually absent. Gastrointestinal mani-
festations (abdominal pain, vomiting) frequently reported
in patients with DKA are not part of HHS; thus the pres-
ence of abdominal pain in patients without significant met-
abolic acidosis needs to be investigated.53 In some patients,
focal neurologic signs (hemiparesis, hemianopsia) and sei-
zures (partial motor seizures more common than general-
ized) may be the dominant clinical features, resulting in a
common misdiagnosis of stroke. Despite the focal nature
of neurologic findings, the neurologic manifestations often
reverse completely after correction of the metabolic dis-
order. Neurologic symptoms of encephalopathy are com-
monly seen when serum sodium levels exceed 160 mEq/L
or when the calculated total and effective osmolalities are
higher than 340 and 320 mOsm/kg H2O, respectively.
Laboratory Findings
The initial diagnostic criteria were reported by Gerich103
and Arieff and Carroll127 and included a blood glucose
concentration greater than 600 mg/dL, a serum osmo-
lality greater than 350 milliosmols/liter, and a serum
acetone reaction no greater than 2+. In the original
case series by Gerich103 and Arieff and Carroll,127 the
mean plasma osmolarity in comatose patients was ∼380
mosm/L compared to ∼320 to 330 mosm/L in conscious
814 PART 5  DIABETES MELLITUS
PROTOCOL FOR MANAGEMENT OF ADULT PATIENTS WITH HYPERGLYCEMIC HYPEROSMOLAR STATE (HHS)
IV fluids
Administer 0.9% NaCl
(500–1000 ml/hr)
during the first 1–2 hrs
Evaluate corrected serum Na+
Na+ Na+
Serum Serum Na+ Serum
high low
normal
0.45% NaCl at 250–500 0.9% NaCl at 250–500
mL/hr depending on state mL/hr depending on state
of hydration of hydration
When serum glucose reaches 200 mg/dl
Change to 5% dextrose with 0.45% NaCl and
decrease insulin to 0.05–0.1 U/kg/hr to maintain
serum glucose ~200 mg/dl until effective osmolality
≤310 mOsm/Lkg and patient is mentally alert.
*Resolution of HHS = serum glucose < 250 mg/dl and effective plasma osmolality < 310 mOsm/kg
Figure 46-3  Protocol for management of patients with hyperglycemic hyperosmolar state (HHS).
subjects.103,127,128 The importance of increased serum
osmolality in the clinical presentation and prognosis of
patients with HHS is well established. Altered sensorium
(lethargy, stupor, coma) correlates better with hyperos-
molality than with the patient’s age or the severity of
acid-base disturbance. The original formula to calculate
serum osmolarity was Sosm = 2 [Na (mEq/L)] + glucose
(mg/dL)/18 + BUN (mg/dL)/2.8). In recent years, the total
serum osmolality formula has been replaced by “effec-
tive” serum osmolality (see Table 46-2).23
The American Diabetes Association Position Statement
diagnostic criteria for HHS are a plasma glucose concen-
tration >600 mg/dL, a serum osmolality >320 mOsm/
kg, and the absence of ketoacidosis,1 (see Table 46-1).
Although by definition, patients with HHS have a serum
pH greater than 7.3, a serum bicarbonate greater than 18
mEq/L, and negative ketone bodies in urine and plasma,
mild ketonemia may still be present. Approximately 50%
of patients with HHS have an increased anion gap meta-
bolic acidosis as the result of concomitant ketoacidosis
and/or an increase in serum lactate levels.
Treatment
Therapeutic measures for HHS are similar to those recom-
mended for patients with DKA (Fig. 46-3). In general, the
treatment of HHS should be directed at replacing volume
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Insulin Potassium
Regular, 0.1 U/kg as IV bolus If serum K+ is <3.3 mEq/L,
hold insulin and give 10–20
mEq per hour of KCl until
serum K+ ≥3.3 mEq/L
0.1 U/kg/hour IV insulin infusion
If serum K+ >5.0 mEq/L,
do not give K+ but check
serum K+ q 2 hr
Check serum glucose every 1–2 hours.
When serum glucose reaches 200 mg/dl
If serum K+ between 3.3
and 5.0 mEq/L, give 20-30
mEq of KCl in each liter of
IV fluid to keep serum K+ at
4–5 mEq/L
Check Chem 7 every 2–4 hrs until resolution of HHS. Initiate SC
insulin when the patient is alert and can eat. Identify and treat
precipitating cause.
deficit, correcting hyperosmolality and electrolyte dis-
turbances, and managing the underlying illness that may
have precipitated metabolic decompensation.129 Patients
with HHS may be severely dehydrated, with an average
fluid deficit of 8 to10 liters. Aggressive fluid replacement
with normal saline at a rate of 1000 mL/hour for the
first 2 to 3 hours is the usual recommendation, followed
by 0.45% saline at a rate of 200 to 500 mL/hour. Insulin
treatment does not need to be aggressive if fluid replace-
ment is vigorously pursued. Insulin is administered by
an initial bolus of 0.1 unit/kg followed by a continu-
ous intravenous infusion calculated to deliver 0.1 unit/
kg/hour, and continued at this rate until blood glucose
has decreased to approximately 250 to 300 mg/dL. At
this time, intravenous fluids should be changed to dex-
trose-containing solutions (D5%) and the insulin dose
should be decreased by 50% (0.05 units/kg/hour) or to 2
to 3 units/hour. Thereafter, the rate of insulin adminis-
tration is adjusted to maintain a blood glucose level of
∼200 mg/dL. Using this protocol, we have reported that
the mean duration of treatment in HHS for serum glu-
cose levels to decrease to the target range is ∼11 hours.7
Intravenous insulin infusion is usually continued until
the patient is hemodynamically stable, the level of con-
sciousness is improved, and the patient is able to toler-
ate food intake. Although most patients require insulin
 46  HYPERGLYCEMIC CRISES: DIABETIC KETOACIDOSIS AND HYPERGLYCEMIC HYPEROSMOLAR STATE
therapy after recovery from HHS, some patients could be
managed with diet alone and/or diet plus an oral hypogly-
cemic agent during the initial admission or shortly after
presentation.3,130
Increased serum potassium is commonly found in
patients with HHS despite severe total body potassium
depletion. Hyperglycemia and hyperosmolality cause a
shift of potassium from the intracellular compartment
into plasma3,130 and may contribute to a false estimate
of total body potassium. The serum potassium deficit in
patients with HHS is estimated ∼3 to 5 mEq/L of body
weight.3,130 The principles of potassium replacement in
HHS are the same as those in DKA. We recommend that
potassium replacement be initiated after serum levels
fall below 5.5 mEq/L, with the goal to maintain a serum
potassium concentration within the normal range of 4 to
5 mEq/L.
Complications
Venous Thromboembolic Events (VTE)
Arterial and venous thrombosis have been described in
patients with HHS.131 Patients with type 2 diabetes are
hypercoagulable compared to normal subjects;132 how-
ever, uncomplicated diabetes is not an independent risk
factor for incident VTE.133 The risk for thromboembolic
events is higher in patients with HHS.4,127,131,134-136 In a
retrospective review of 426, 831 cases of VTE, the over-
all incidence of thromboembolism among patients with
hyperosmolarity was 1.7%.134 Severe dehydration, along
with hyperviscosity and hypotension, may predispose
to intravascular clotting, and heparinization during the
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815
initial phase of treatment has been considered by some
authors98,131,137; however, this has not been evaluated
prospectively.
Rhabdomyolysis
Hyperosmolality alone could be a risk factor for rhab-
domyolysis.138,139 Rumpf and colleagues described in
1981 the association of acute rhabdomyolysis with myo-
globinuric renal failure in a patient with HHS.140 Since
then, several cases have been reported in adult and pedi-
atric patients. Subclinical rhabdomyolysis appears to be a
common finding in HHS, and there seems to be a linear
relationship between serum osmolarity, serum sodium,
and the level of creatine kinase increase.141 Rhabdo-
myolysis is a potentially life-threatening complication
associated with acute kidney failure, hyperkalemia, hypo-
calcemia, hyperphosphatemia, compartment syndrome,
disseminated intravascular coagulation, and multi-organ
failure.96,142,143
Prevention
The most common precipitating causes of HHS are infec-
tion and intercurrent illness. Improved outpatient treat-
ment programs, glucose monitoring, and better adherence
to self-care should result in reduced admission of patients
with hyperglycemic crises.
  
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